Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons

Enriori, Pablo J.; Evans, Anne E; Sinnayah, Puspha; Jobst, Erin E; Tonelli-Lemos, Luciana; Billes, Sonja K; Glavas, Maria M.; Grayson, Bernadette E.; Perelló, Mario; Nillni, Eduardo A.; Grove, Kevin L.; Cowley, Michael A.

doi:10.1016/j.cmet.2007.02.004

Cited by 488 publications

(467 citation statements)

References 56 publications

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“…Although this model does not lead to total loss of Ift88, it eliminates confounding effects of cilia loss during development, an advantage that the previously used POMC-Cre transgene does not possess (23,35). It was previously shown that other obese leptinresistant animals regain leptin sensitivity on regulation of body composition through controlled feeding (36,37). Furthermore, the study presented here allowed for the repetitive assessment of leptin sensitivity in the same cohort of mice at different adiposity and leptin levels.…”

Section: Discussionmentioning

confidence: 93%

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

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Section: Discussionmentioning

confidence: 93%

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…High fat feeding can affect a variety of brain and peripheral pathways involved in energy balance [25,26] including beta adrenergic function [21]. Furthermore, these effects are dependent upon genetic vulnerability to diet-induced obesity and are correlated with lipid and glucose metabolism [39,46].…”

Section: Introductionmentioning

confidence: 99%

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

et al. 2009

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The vgf gene regulates energy homeostasis and the VGF-derived peptide TLQP-21 centrally exerts catabolic effects in mice and hamsters. Here, we investigate the effect of chronic intracerebroventricular (icv) injection of TLQP-21 in mice fed high fat diet (HFD). Fast weightgaining mice injected with the peptide or cerebrospinal fluid were selected for physiological, endocrine, and molecular analysis. TLQP-21 selectively inhibited the increase in body weight and epididymal white adipose tissue (eWAT) weight induced by HFD in control animals despite both groups having a similar degree of hyperphagia. TLQP-21 normalized the increase in leptin and decrease in ghrelin while increasing epinephrine and epinephrine/norepinephrine ratio when compared to values in controls. Finally, HFD-TLQP-21 mice showed a selective increase of eWAT b3-adrenergic receptor mRNA. Peroxisome-proliferatoractivated-receptor-d and hormone-sensing-lipase mRNA were also upregulated. In conclusion, chronic icv infusion of TLQP-21 prevented the early phase of diet-induced obesity despite overfeeding. These effects were paralleled by activation of catabolic pathways within the eWAT. Our results further support a role for TLQP-21 as a catabolic neuropeptide.

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“…Our laboratory has extensive experience and expertise in using a male mouse model for acute glycemic control studies (Enriori et al, 2007). We further tested the acute effects of ZNS on blood glucose using male C57BL/6J mice (5 animals per treatment group 2 h post drug treatment) via saphenous vein bleeds in order to investigate the mechanism of the effect of ZNS treatment on OLZ-associated glucose dysregulation and to determine to what extent increased blood glucose was weight-related.…”

Section: Drug Treatmentfblood Glucosementioning

confidence: 99%

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

Wallingford

Sinnayah

Bymaster

et al. 2008

Neuropsychopharmacol

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Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.

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Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons

Cited by 488 publications

References 56 publications

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

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